The study looked at a brain protein called AKAP150 and found that when its fatty‑acid attachment (palmitoylation) is increased, seizures get worse in mice. Blocking the protein or stopping its palmitoylation reduced seizure severity and frequency. This work points to AKAP150 as a possible drug target for epilepsy, but it does not involve the peptide palmitoyl‑dipeptide‑6.

Epilepsy is a chronic and refractory neurological disorder, with drug resistance remaining a major challenge. Identifying new therapeutic targets could facilitate the development of more effective anti-seizure medications. AKAP79/150, a member of A-Kinase Anchoring Proteins (AKAPs) family, plays a critical role in synaptic transmission and plasticity. Although its implication in early epileptogenesis has been reported, its role in epilepsy progression remains unclear. In this study, using a kainic acid (KA)-induced epilepsy mouse model, we found that the expression and palmitoylation of AKAP150 in the hippocampus were significantly upregulated during epilepsy development. Silencing AKAP150 by the right intracerebroventricular (ICV) siRNA injections or inhibiting its palmitoylation by 2-bromohexadecanoic acid attenuated KA-induced epilepsy, as evidenced by reduced seizure severity, duration, and frequency of spontaneous recurrent seizures within 14 days. Mechanistically, AKAP79/150 interacts with protein kinase C (PKC) to suppress KCNQ expression, thereby diminishing inhibitory M-currents and contributing to epileptogenesis. Our findings reveal the pivotal role of AKAP79/150 in epilepsy progression and highlight its potential as a therapeutic target for epilepsy intervention.